Aspirin inhibits endometrial fibrosis by suppressing the�TGF‑β1‑Smad2/Smad3 pathway in intrauterine adhesions

Zhang, Zihui; Li, Shuang; Deng, Jie; Yang, Shaorong; Xiang, Ziwu; Guo, Hongyan; Xi, Hongli; Sang, Ming; Zhang, Wei

doi:10.3892/ijmm.2020.4506

Cited by 24 publications

(25 citation statements)

References 37 publications

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“…Also, ERK1/2 inhibition attenuated fibrotic remodeling after myocardial infarction (Luo et al 2017 ). Although the structurally similar aspirin has been shown to suppress ERK1/2 and SMAD2/3 signaling (Li et al 2018 ; Zhang et al 2020 ), systemic side effects might overshadow the potential benefits. For this reason, we explored the effects of mesalazine on SMAD2/3 and ERK1/2 activation.…”

Section: Resultsmentioning

confidence: 99%

Repurposing mesalazine against cardiac fibrosis in vitro

Hoffmann

Kant

Emig

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ induces fibroblast activation and differentiation into myofibroblasts that secrete excessive extracellular matrix proteins leading to stiffening of the heart, concomitant cardiac dysfunction, and arrhythmias. However, effective pharmacotherapy for preventing or reversing cardiac fibrosis is presently unavailable. Therefore, drug repurposing could be a cost- and time-saving approach to discover antifibrotic interventions. The aim of this study was to investigate the antifibrotic potential of mesalazine in a cardiac fibroblast stress model. TGFβ was used to induce a profibrotic phenotype in a human cardiac fibroblast cell line. After induction, cells were treated with mesalazine or solvent control. Fibroblast proliferation, key fibrosis protein expression, extracellular collagen deposition, and mechanical properties were subsequently determined. In response to TGFβ treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary αSMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGFβ led to increased cell stiffness and adhesion, which were reversed by mesalazine treatment. Collagen 1 expression and deposition—key drivers of fibrosis—were significantly increased upon TGFβ stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NFκB translocation, were identified as potential modes of action. The current study provides experimental pre-clinical evidence for antifibrotic effects of mesalazine in an in vitro model of cardiac fibrosis. Furthermore, it sheds light on possible mechanisms of action and suggests further investigation in experimental and clinical settings.

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Section: Resultsmentioning

confidence: 99%

Repurposing mesalazine against cardiac fibrosis in vitro

Hoffmann

Kant

Emig

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Therefore, subsequent IUA management is considered necessary when IUA occurs. Thus far, there have been many publications addressing the topic of the management of IUA [ 23 , 24 , 26 , 27 , 28 , 29 , 30 , 35 , 40 , 43 , 57 , 58 , 59 , 62 , 64 , 131 , 132 , 133 , 134 , 135 , 136 , 138 , 139 , 140 , 141 , 142 , 155 , 164 , 165 , 166 , 167 , 168 ].…”

Section: Future Vision Of Iua Managementmentioning

confidence: 99%

Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision

Lee

Liu

Chen

et al. 2021

IJMS

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Intrauterine adhesion (IUA), and its severe form Asherman syndrome (Asherman’s syndrome), is a mysterious disease, often accompanied with severe clinical problems contributing to a significant impairment of reproductive function, such as menstrual disturbance (amenorrhea), infertility or recurrent pregnancy loss. Among these, its correlated infertility may be one of the most challenging problems. Although there are many etiologies for the development of IUA, uterine instrumentation is the main cause of IUA. Additionally, more complicated intrauterine surgeries can be performed by advanced technology, further increasing the risk of IUA. Strategies attempting to minimize the risk and reducing its severity are urgently needed. The current review will expand the level of our knowledge required to face the troublesome disease of IUA. It is separated into six sections, addressing the introduction of the normal cyclic endometrial repairing process and its abruption causing the formation of IUA; the etiology and prevalence of IUA; the diagnosis of IUA; the classification of IUA; the pathophysiology of IUA; and the primary prevention of IUA, including (1) delicate surgical techniques, such as the use of surgical instruments, energy systems, and pre-hysteroscopic management, (2) barrier methods, such as gels, intrauterine devices, intrauterine balloons, as well as membrane structures containing hyaluronate–carboxymethylcellulose or polyethylene oxide–sodium carboxymethylcellulose as anti-adhesive barrier.

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“…Recently, stem cell-derived exosomes were found to reverse the elevated expression of TGF- β 1 and Smad mRNA in endometrial epithelial cells and an animal model of IUA [ 8 ]. Moreover, the suppression of the TGF- β 1/Smad pathway by drug intervention is proposed to inhibit endometrial fibrosis [ 9 ]. TGF- β 1 is activated in the human endometrium by serine kinases; once activated, it, in turn, activates Smad2, Smad3, and Smad4 [ 10 ], which mediate most profibrotic activities [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Tiaoshen Tongluo Attenuates Fibrosis by Modulating the TGF-β1/Smad Pathway in Endometrial Stromal Cells and a Rat Model of Intrauterine Adhesion

Niu

Miao

Zhan

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Intrauterine adhesion (IUA) is a serious complication caused by excessive fibrosis resulting from endometrial repair after trauma. The traditional Chinese medicine Tiaoshen Tongluo recipe (TTR) contains ingredients associated with the alleviation of fibrosis. The transforming growth factor-β1 (TGF-β1)/Smad pathway is thought to mediate fibrosis in IUA. In this study, we evaluated the influence of TTR on endometrial fibrosis in a rat model of IUA and in TGF-β1-stimulated endometrial stromal cells (ESCs). TTR was found to alleviate the level of endometrial fibrosis in a rat model of IUA. A higher number of collagen fibers and greater damage were observed in the endometrial tissue of untreated rats compared to those treated with TTR. The expression of TGF-β1, Smad2, Smad3, and Smad4 was upregulated following IUA, whereas Smad7 expression was downregulated. TTR lowers the expression of TGF-β1, Smad2, Smad3, and Smad4 but increases the expression of Smad7 in vivo, indicating that TTR can modulate the expression of the TGF-β1/Smad pathway to mediate fibrosis. In ESCs, the phosphorylation of Smad2 and Smad3 and upregulation of Smad4 were induced by TGF-β1 whereas the expression of Smad7 was inhibited. Administration of TTR reduces the phosphorylation of Smad2 and Smad3, increases Smad4 expression induced by TGF-β1, and promotes the expression of Smad7. TTR modulates the TGF-β1/Smad pathway to alleviate the generation of fibrotic tissue in response to IUA.

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Aspirin inhibits endometrial fibrosis by suppressing the�TGF‑β1‑Smad2/Smad3 pathway in intrauterine adhesions

Cited by 24 publications

References 37 publications

Repurposing mesalazine against cardiac fibrosis in vitro

Repurposing mesalazine against cardiac fibrosis in vitro

Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision

Tiaoshen Tongluo Attenuates Fibrosis by Modulating the TGF-β1/Smad Pathway in Endometrial Stromal Cells and a Rat Model of Intrauterine Adhesion

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